Clinical practice and outcome of patients with elderly‐onset ulcerative colitis: Insights from a nationwide claims database study in Japan

Abstract Background and Aim The number of older patients with ulcerative colitis is increasing; however, limited data exist regarding the differences between elderly‐ and non‐elderly‐onset ulcerative colitis. We aimed to compare the clinical practice and course of elderly‐onset ulcerative colitis with those of non‐elderly‐onset ulcerative colitis. Methods We selected older patients with ulcerative colitis and divided them into the elderly‐ and non‐elderly‐onset ulcerative colitis groups according to their age at onset. We compared the cumulative systemic steroid‐free, molecular targeting drug‐free, and surgery‐free rates between the two groups. We performed a multivariate analysis to identify the clinical factors related to systemic steroid administration, the use of molecular targeting drugs, surgery, and death. Results We collected data of 2669 and 277 elderly and non‐elderly‐onset ulcerative colitis patients, respectively. The cumulative systemic steroid‐free rate of elderly‐onset ulcerative colitis was significantly lower than that of non‐elderly‐onset ulcerative colitis. However, no difference was observed in the cumulative molecular targeting drugs and surgery‐free rates between the two groups. Elderly‐onset ulcerative colitis significantly increased the risk of systemic steroid administration and death but not the use of molecular targeting drugs and surgery. Conclusion The disease severity of ulcerative colitis and clinical practice may not differ between the elderly‐ and non‐elderly‐onset groups. However, elderly‐onset ulcerative colitis was associated with increased mortality risk. Thus, we need to pay attention to the patients' condition and appropriate timing of surgery for patients with elderly‐onset ulcerative colitis.


Introduction
2][3] Recently, the number of patients diagnosed with UC has been increasing. 4Japan is an aging society, with the population aged ≥65 years of 36 236 000 (29.0% of the total population). 5As an aging society progresses, the number of older patients with UC is expected to increase.7][8] Consequently, the number of older patients with UC is increasing in various countries, 9,10 including Japan. 11,12lder patients with UC are divided into two types based on their age at onset: (i) patients who develop UC in older ages (elderly-onset UC [EOUC]) and (ii) those who develop UC at a younger age and become older (non-elderly-onset UC [NEOUC]).However, limited data exist regarding the differences between EOUC and NEOUC.Older patients with UC generally require careful treatments than younger patients because of frailty and high risk of complications.Therefore, clarifying the clinical practices for older patients and differences between EOUC and NEOUC is essential.
The number of older patients with UC in a single center is relatively small to analyze; thus, a single-center study may be inadequate.4][15][16][17][18][19][20] Therefore, this study aimed to clarify the clinical practice of EOUC and compare the differences in clinical course between EOUC and NEOUC using a nationwide claims database in Japan.

Methods
Data source.In this study, we contracted DeSC Healthcare, Inc. (https://desc-hc.co.jp/en), a joint company providing various healthcare services, and obtained permission to use their dataset comprising the prescription claim receipts of patients with UC.This dataset contains anonymized inpatient and outpatient prescription claims records, which include age, sex, medical treatment, surgery, and clinical diagnosis, based on the International Classification of Diseases 10th version (ICD-10) from a health insurance association in Japan from April 2014 to February 2022.

Extraction of eligible patients and data collection.
Figure 1 shows the selection flowchart of eligible patients from the DeSC Healthcare database.We identified UC cases using ICD-10 code K51.We excluded the following cases: (i) suspicious cases containing the word "suspicious" and (ii) cases that had Crohn's disease in their diagnosis.Subsequently, we extracted cases that were assumed to have newly developed UC based on the definitions described below.The DeSC dataset provided the data on the patients' birth year and month, which enabled the estimation of patients' age at UC onset.We eventually selected patients aged ≥65 years at the end of the observation period and divided the eligible patients into two groups as follows: (i) patients who developed UC at age ≥65 years (elderly-onset [EO] group) and (ii) those who developed UC at age <65 years and became aged ≥65 years during the observation period (non-elderly-onset [NEO] group).
The definition of elderly is ≥65 years based on the World Health Organization classification. 21e collected the following patient data from the DeSC dataset: sex, start and end dates of observation, and surgery.Information regarding prescribed medications including 5aminosalicylic acid (5-ASA), systemic steroid administration (prednisolone), immunomodulators (azathioprine and 6-mercaptopurine), molecular targeting drugs (MTDs) including biologics (infliximab, adalimumab, golimumab, ustekinumab, and vedolizumab) and small-molecule agents (tofacitinib, tacrolimus, and cyclosporine) were also collected.
Definitions of new prescription and new development of UC.The definitions described below are similar with those of our previous study. 22We defined a "new" prescription for each drug as no prescription within 26 weeks before the first prescription date of the medicine during the observation period.Other types of prescriptions were defined as "old" prescriptions.
Prescription was defined as discontinuation in cases of no prescription for >13 weeks from the next scheduled prescription date.The next scheduled prescription date differed between drugs.For instance, the next scheduled prescription date for ustekinumab was 12 weeks after the last prescription date (infliximab and vedolizumab were 8 weeks, adalimumab and golimumab were number of prescriptions Â 14 days, and other drugs were prescription days).
We also assumed cases in our study that had both (i) new prescription of either 5-ASA, systemic steroid, or topical steroid drugs and (ii) no old prescription of such drugs during the observation period as new-onset UC.Based on this assumption, we estimated the age at UC onset.Data and statistical analyses.Geographical data, medications including the number of MTD use and systemic steroid prescription days, and clinical event (surgery and death) rates were compared between the EO and NEO groups using the chisquare test.We compared the cumulative surgery-free, systemic steroid-free, MTD-free, and cumulative treatment persistence rates of the first MTD between the EO and NEO groups using the Kaplan-Meier method.We also conducted a comparative analysis of the efficacy of combination therapy involving infliximab and azathioprine, focusing on the treatment persistence rate as assessed through the Kaplan-Meier method in both EO and NEO groups.Combination therapy was defined as the confirmation of azathioprine prescription concurrent at the initiation of infliximab.
Multivariate logistic regression analysis was performed to identify the clinical factors related to systemic steroid administration, use of MTDs, surgery, and death.Statistical significance was set at P < 0.05.All analyses were performed using the JMP Pro17 software (SAS Institute, Tokyo, Japan).

Ethics approval and patient consent statement.
The study protocol was reviewed and approved by the Ethics Committee of the Tohoku University Graduate School of Medicine (2022-1-412).The requirement for informed consent was waived because of the anonymity of patient data.

Results
Background of the study population.We extracted the data of 2946 older patients with UC, of whom 2669 were assigned to the EO group and 277 to the NEO group.Patient characteristics are summarized in Table 1.The mean observation period was 1629.6 days.The administration rates of systemic steroids and MTD were 34.2% (1008 of 3946) and 7.0% (205 of 2669), respectively.The surgery rate was 2.2% (65 of 2946).
Comparison of geographical data, medications, and clinical event rates between the elderly-and non-elderly-onset groups.Table 2 shows the comparison between the EO and NEO groups.No significant differences were observed in the male/female ratio, academic hospital rate, administration rates of systemic steroids and MTDs, the number of MTD use, prescription days of systemic steroid, or surgery rate between the two groups.Furthermore, no difference was observed in the number of MTDs between the EO and NEO groups.The rate of infliximab as the first MTD in the EO group was lower than that in the NEO group (31.4% vs 50.0%), whereas vedolizumab was more frequently selected in the EO group compared with the NEO group (19.5% vs 5.0%).The mortality rate in the EO group was higher than that in the NEO group (4.5% vs 0.72%, P = 0.0011).
Differences in long-term prognosis after onset between the elderly-and non-elderly-onset groups.The cumulative systemic steroid-free, MTD-free, and surgery-free rates in the EO and NEO groups are shown in Figure 2. The cumulative systemic steroid-free rate at 5 years after onset in the EO group was significantly lower than that in the NEO group (57.6% vs 68.6%, P = 0.0030), whereas no significant difference was observed in the cumulative MTDs or surgery-free rates between the two groups (P = 0.29 and P = 0.61, respectively).
In patients who received MTDs, no difference was observed in the cumulative treatment persistence rate of the first MTDs between the EO and NEO groups (Fig. 3a).The cumulative treatment persistence rates for each MTD are shown in Figure 3b.There was no difference in the treatment persistence days among each MTD (P = 0.13).Figure 4 illustrates the outcomes of comparing the combination therapy comprising infliximab and azathioprine with infliximab monotherapy.In the EO group, no significant difference was observed in the cumulative infliximab persistence rate between patients receiving infliximab with and without azathioprine (P = 0.90, Fig. 4a).Similarly, in the NEO group, a similar result was obtained (P = 0.050, Fig. 4b).

Discussion
This study revealed that the use of systemic steroids, MTDs, and surgery rates did not differ between the EO and NEO groups; however, mortality rate in the EO group was higher than that in the NEO group.Although the cumulative systemic steroid-free rate in the EO group was higher than that in the NEO group, the cumulative MTD-free and surgery-free rates between the EO and NEO groups did not differ.The cumulative treatment persistence rate of the first MTD rate also did not differ between the EO and NEO groups.Multivariate analysis demonstrated that EOUC was a clinical factor that increased the risk of systemic steroid administration and death.Based on our findings, there may not be a significant variance in disease severity between EOUC and NEOU.Our investigation revealed that the cumulative systemic steroid-free rate in the EO group was significantly lower than that in the NEO group, whereas the use of systemic steroids, MTDs, and surgery rates did not differ between the two groups.Moreover, prescription days of systemic steroid or the number of MTD use between the EO and NEO groups did not differ.Additionally, the cumulative infliximab persistence rate did not differ regardless of concurrent azathioprine in both EO and NEO groups.These outcomes collectively suggest a comparable level of disease severity between the two groups.Previous studies investigating the differences between EOUC and NEOUC have reported contradictory results.Several studies have demonstrated that NEOUC has more severe disease activity than EOUC, [23][24][25] whereas one study showed that the rate of severe colitis during the observation period did not differ between EOUC and NEOUC. 8A topical review by the European Crohn's and Colitis Organization also stated that the severity of EOUC and NEOUC was almost similar. 26However, the definitions of elderly in these studies differed.Further prospective studies are warranted to determine whether disease activities of EOUC and NEOUC differ.
Our study also implies that patients with EOUC can avoid surgery using MTDs.Although multivariate analysis revealed that the use of MTDs was a clinical factor that associated with the risk of surgery, surgery and cumulative surgery-free rates did not differ between the EO and NEO groups.A Japanese cohort study reported that patients with EOUC had a higher surgery rate than those with NEOUC. 27Our results may differ from those of this previous study because of the difference in NEOUC definition.Our study investigated the difference between EOUC patients and aged patients with NEOUC (patients who developed UC at age <65 years and became ≥65 years).In contrast, the previous study 27 compared EO (patients who developed UC at age ≥65 years) and younger onset (all patients who developed UC at age <65 years) UCs.Therefore, the number of patients with NEOUC in our study was smaller compared with that of the previous study conducted in Japan. 27Although our study followed up one patient for approximately 4-5 years on average, the difference in surgery rates between EOUC and NEOUC might not The bold value means statistical significance.iv, intravenous injection; po, per os; UC, ulcerative colitis.
have been recognized without a long observation period.A previous review concluded that the indications for surgery in older patients with UC were not different from that of non-older patients with UC 26 .Therefore, further investigations on surgery rates differences between EOUC and NEOUC in longer observation periods are warranted.We observed that the clinical use of MTDs did not differ between the EO and NEO groups, and no significant differences in the number of MTDs administered were observed.Although the breakdown of the first MTD did not differ between the EO and NEO groups, vedolizumab was more frequently selected in the EO group than in the NEO group, whereas infliximab was less frequently selected in the EO group than in the NEO group.Generally, older patients undergoing immunosuppressive therapies easily develop infections and complications due to frailty. 26,28,29One retrospective study reported that older patients with UC who were administered infliximab or adalimumab had a higher rate of severe infections and mortality compared with younger or older patients who were not treated with biologics. 30Another study revealed that oral corticosteroids increased the risk of serious infections. 31Contrastingly, a subanalysis of a phase III trial demonstrated that the safety of vedolizumab in older patients with UC was similar to that in other age groups. 32Therefore, physicians in Japan may select low immunosuppressive therapy for older patients compared with younger patients.
In this study, we observed that the EO group had a higher mortality rate than the NEO group.Our results showed that the average age at the end of observation period of EO groups was higher than that of NEO group (Table 2).Older age itself could contribute to high mortality rate because of various reasons including malignancy and cardiopulmonary diseases.However, the reasons of death in this study were unclear due to the nature of the DeSC database.Another study also reported a high mortality rate similar to our results. 33As described above, older patients are more likely to develop infections and complications, which contribute to a high mortality rate.Furthermore, a retrospective study from Japan showed high mortality rate (26.7%) after urgent surgery in older patients with UC. 34 Thus, we suggest that the patient's condition and appropriate timing of surgery should be considered in older patients with UC.Elective surgery should be considered to the greatest extent possible, even if surgery is inevitable.
This study had some limitations.First, due to the nature of the DeSC dataset, it does not contain detailed clinical information of patients, including blood test data, endoscopic findings, disease extent, and computed tomography, which is necessary to determine the severity of UC.Therefore, we indirectly evaluated disease severity by investigating the rates of systemic steroids, MTDs, and surgery.For the same reason, we could not identify the reason of death.Second, although the DeSC dataset contains a large number of patients, its representativeness is not guaranteed because the rate of academic hospitals is remarkably low.Third, this was a retrospective study.A nationwide prospective study is required to comprehensively evaluate the differences between the EO and NEO groups.Despite these limitations, our analysis revealed differences between EOUC and NEOUC in a large dataset of patients with UC.Our findings are expected to enhance daily clinical practice for managing UC in the elderly and inform future investigations.
In conclusion, the severity and clinical course between the EOUC and NEOUC groups may not significantly differ in the long term after UC onset.The clinical practice for treating UC does not differ between the EOUC and NEOUC groups.However, we need to pay attention to the patient's condition and consider the appropriate timing of surgery when treating older patients with UC because of the high mortality rate in the EOUC groups.Further prospective investigations are warranted to confirm our findings.
Figure 4 The cumulative infliximab persistence rates compared with and without azathioprine.(a).In the EO group, no significant difference was observed in the cumulative infliximab persistence rate between patients receiving infliximab with and without azathioprine (P = 0.90).(b) In the NEO group, no significant difference was observed in the cumulative infliximab persistence rate between patients receiving infliximab with and without azathioprine (P = 0.050).

Figure 1
Figure 1 The flowchart for extraction of eligible patients from the patient claims database of DeSC Healthcare, Inc.

Figure 3
Figure 3 The cumulative treatment persistence rates of the first molecular targeting drug.(a) The cumulative treatment persistence rate of the first molecular targeting drug between elderly-and non-elderly-onset ulcerative colitis was not different (P = 0.36).(b) The cumulative treatment persistence rate of each drug in elderly patients with ulcerative colitis is not different (P = 0.13).

Figure 2
Figure2The Kaplan-Meier curve describing the differences in long-term prognosis between onset age categories.(a) The cumulative systemic steroid-free rates of elderly-and non-elderly-onset ulcerative colitis at 5 years are 57.6% and 68.6%, respectively (P = 0.0030).(b) The cumulative molecular targeting drug-free rates of elderly-and non-elderly-onset ulcerative colitis at 5 years are 88.8% and 92.9%, respectively (P = 0.29).(c) The cumulative surgery-free rates of elderly-and non-elderly-onset ulcerative colitis at 5 years are 97.5% and 98.5%, respectively (P = 0.29).
† of the association among clinical factors and clinical events in patients with ulcerative colitis Clinical factors Number of patients n Cox proportional hazard model.The bold value means statistical significance.CI, confidence interval; UC, ulcerative colitis.R Moroi et al.Older-onset ulcerative colitis

Table 1
Background of older patients with UC iv, intravenous injection; po, per os; UC, ulcerative colitis.R Moroi et al.Older-onset ulcerative colitis

Table 2
Comparisons of backgrounds, treatment, and outcomes between elderly-and non-elderly-onset UC